Engineering CXCL12 Biomimetic Decoy‐Integrated Versatile Immunosuppressive Nanoparticle for Ischemic Stroke Therapy with Management of Overactivated Brain Immune Microenvironment

Abstract

Following ischemic stroke, brain‐resident activated microglia and peripherally infiltrated inflammatory cells create a complicated and overactivated brain immune microenvironment, which causes neuron death and dramatically hinders neurological functional recovery. Herein, an engineering CXCL12 biomimetic decoy‐integrated versatile immunosuppressive nanoparticle (VIN) for management of the overactivated brain immune microenvironment is reported. The shell of VIN (membrane of CXCR4 overexpressed mesenchymal stem cells), can not only improve the homing of nanoparticles to the cerebral ischemic lesions, but also efficiently adsorb and neutralize CXCL12 to cut off infiltration of peripheral‐neutrophils and mononuclear macrophages. The loaded A151 (cGAS inhibitor, telomerase repeat sequences) can inhibit cGAS‐STING pathway in microglia, leading to microglia polarization toward an anti‐inflammatory M2‐like phenotype. Interestingly, A151 can be efficiently loaded onto the polydopamine nanospheres (PDA, the core of VIN) through the bridge of Zn2+. In the inflammatory site, PDA is oxidized by reactive oxygen species (ROS), with the disappearance of Zn2+ complexation effect, and then A151 realizes a controlled release. In a model of rat ischemic stroke, VIN integrates inflammation tropism, peripherally inflammatory cells filtrate, brain‐resident activated microglia polarization, as well as, ROS scavenging, exerting outstanding therapeutic effects on ameliorating the mortality, reducing the infarct volume, and protecting neurogenic functions of neurons.

Intrinsically Bioactive Manganese–Eumelanin Nanocomposites Mediated Antioxidation and Anti‐Neuroinflammation for Targeted Theranostics of Traumatic Brain Injury

“…Recent studies reported that macrophage repolarization from M1 to M2 relieved the inflammation and promoted neuro‐protection. [ 11,40 ] Although natural melanin nanoparticles were reported to polarize tumor‐associated macrophages from M2 to M1 in tumors, [ 41 ] emerging evidence showed that melanin nanoparticles could repolarize M1 to M2 macrophages in acute liver injury, [ 33 ] myocardial infarction, [ 42 ] and acute kidney injury, [ 43 ] which may be attributed to the different microenvironments. We investigated the anti‐inflammatory effects of AMEC using macrophages which were double labeled with F4/80 and CD11b in the injury site.…”

Neuroinflammation of microglia polarization in intracerebral hemorrhage and its potential targets for intervention

“…Moreover, Jiang et al ( 2021 ) have elucidated that cGAS knockdown improved M2 phenotype polarization of microglia to attenuate microglial inflammatory response by hindering the cGAS-STING signal axis in mice with stroke, highlighting that such signal axis can be used as a potential therapeutic target. Subsequently, the experiment performed by Shi et al ( 2022 ) also demonstrated that inhibiting the cGAS-STING pathway through a cGAS inhibitor integrated versatile immunosuppressive nanoparticle in microglia contributed to improving an anti-inflammatory phenotype polarization in rats following stroke.…”

The Link between Stroke Risk and Orodental Status—A Comprehensive Review

“…Inflammatory cytokines are then released by activated microglia and peripheral leucocytes, which enhance the inflammatory response. Studies have reported that elevated inflammatory markers are associated with the risk of stroke recurrence and less favorable outcomes [ 39 , 40 ]. Several events such as reperfusion of tissue, oxidative stress, and microglial activity can promote cell death in the penumbra region, which can lead to secondary neuronal death and further increased damage to stroke area [ 41 ].…”